1,2,4-Triazoles

ABSTRACT

Triazoles substituted at the 3 and 5 positions having an optional substituent in the 1 position are provided. Methods of preparing the novel substituted triazoles are described. The substituted triazoles are useful as anti-gout and anti-hyperuricemic agents. Compositions useful in the treatment of gout and hyperuricemia containing a substituted triazole as the active ingredient are also provided.

BACKGROUND OF THE INVENTION

This is a continuation, of copending application Ser. No. 543,563 filedJan. 23, 1975 abandoned which in turn is a division of application Ser.No. 392,842, filed Aug. 29, 1973 now U.S. Pat. No. 3,879,404, which inturn is a division of U.S. Ser. no. 269,685, filed July 7, 1972 nowabandoned, which in turn was a continuation-in-part of application Ser.No. 75,785 filed Sept. 25, 1970, now abandoned.

FIELD OF THE INVENTION

The invention relates to a class of triazoles which are substituted inthe 3 and 5 positions and bear optional substituents in the 1 position.The substituent in the 1 position is an alkyl, alkanoyl, carbamoyl orbenzyl group. The substituents in the 3 and 5 positions are aryl orheteroaryl groups, or a group derived therefrom.

DESCRIPTION OF THE PRIOR ART

The herein-described substituted triazoles have utility as anti-gout andanti-hyperuricemic agents.

Gout is a condition affecting humans and lower animals, particularlybirds and reptiles, which is characterized by perversion of the purinemetabolism resulting in an excess of uric acid in the blood, by attacksof acute arthritis, and by formation of chalky deposits in thecartilages of the joints. These deposits are made up chiefly of urates,or uric acid. Hyperuricemia is a condition characterized by an excess ofuric acid in the blood.

Uric acid serves no biochemical function in the body and is merely anend product of purine metabolism. It is well known in the art that thepurine bases adenine and guanine, which play key roles in a wide varietyof chemical processes, both give rise to uric acid in the body. Adenylicacid and guanylic acid are converted to the free purine bases bydestructive metabolic enzymes. A portion of the free purine bases isconverted to purine ribonucleotides and the remainder is degraded to thefree bases xanthine and hypoxanthine. A single enzyme, xanthine oxidase,converts both xanthine and hypoxanthine to uric acid for excretion.

Although human purine biosynthesis can be inhibited at the stage offormyl glycinimide ribotide by the glutamine antagonists azaserine and6-diazo-5-oxo-1-norleucine, a high incidence of undesirable side effectsprecludes their being used clinically for this purpose. In recent years,substantial progress has been made in attempting to control theexcessive levels of uric acid in patients afflicted with gout throughthe use of pharmaceutical agents. Uric acid synthesis has beeneffectively blocked by the use of allopurinol,4-hydroxypyrazolo-[3,4-d]-pyrimidine, a compound which is a structuralisomer of hypoxanthine. Allopurinol acts as a specific inhibitor of theenzyme xanthine oxidase, which is responsible for the conversion of bothhypoxanthine and xanthine to uric acid. As a direct result of theadministration of this compound to patients afflicted with gout, part ofthe uric acid which would normally end up in the urine is replacedinstead by the oxypurines, hypoxanthine and xanthine, thus greatlyreducing the content of uric acid in serum and urine. Azathioprine hasalso been employed in patients afflicted by gout to inhibit theexcessive purine synthesis, which tends to produce abnormal amounts ofuric acid. Other compounds, such as acetylsalicylic acid,thiophenylpyrazolidine, and phenylbutazine have been employed in thetreatment of gout. Many of the existing compounds used in the treatmentof gout, however, relieve the inflammation and other symptoms connectedtherewith but have no effect on the conditions which give rise to goutyarthritis or hyperuricemia. Thus, there is still a need for compoundswhich can be employed in the prophylactic treatment of gout as well asfor the treatment of other abnormal conditions associated withhyperuricemia.

The substituted triazoles which are the subject of this invention havebeen found to be effective anti-gout and anti-hyperuricemic agents inthat they will inhibit the action of the enzyme xanthine oxidase andthus reduce the content of uric acid in serum and urine. In addition totheir use as anti-gout and anti-hyperuricemic agents, certain of thetriazoles exhibit diuretic and hypotensive activity.

SUMMARY OF THE INVENTION

An object of this invention is to provide novel substituted1,2,4-triazoles which are useful anti-gout, anti-hyperuricemic andhypotensive agents. Methods of preparing the novel substituted triazolesare described. Also within the scope of the invention are the alkalimetal and alkaline earth metal salts of the triazoles, and in thosecases where the substituent in the 3 or 5 position contains at least onebasic nitrogen, the pharmaceutically acceptable quaternary and acidaddition salts.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The novel 1,2,4-triazoles which are the subject of this invention may bedepicted as follows: ##STR1## wherein R₁ is

hydrogen, lower alkyl, lower alkanoyl, aralkyl, for example, benzyl ormenaphthyl and the like, carbamoyl, lower alkyl carbamoyl or di- lowercarbamoyl;

R₃ is

phenyl,

naphthyl, as for example, 1-naphthyl or 2-naphthyl and the like,

pyridylmethyl, as for example, picolyl,

a five or six membered heterocycle containing from 1-3 oxygen, nitrogenor sulfur atoms as, for example,

quinolyl,

cinnolyl,

pyridyl,

pyrazinyl,

furyl,

pyrimidinyl,

pyridazinyl, or

thienyl, or

substituted phenyl containing from 1- 3 substituents selected from

halogen, such as chlorine, bromine or iodine,

lower alkyl as, for example, methyl, ethyl or propyl and the like,

amino,

di- lower alkylamino wherein the lower alkyl moiety contains from 1- 5carbon atoms as, for example, methyl, ethyl, propyl, butyl or pentyl andthe like,

sulfamoyl,

lower alkylsulfamoyl as, for example, methanesulfamoyl orethanesulfamoyl and the like,

lower alkoxy as, for example, methoxy, ethoxy or propoxy and the like,or

lower alkanoylamino as, for example, formamido, acetamido, propionamidoor butyramido and the like, and

R₅ is pyridyl, such as 2-pyridyl, 3-pyridyl or 4-pyridyl, pyrimidinyl orpyrazinyl;

provided, that when R₅ is pyridyl R₃ is other than pyridyl, phenyl oralkylphenyl.

When the compounds of this invention contain a lower alkyl radical, itis preferred that such radical contain from 1-5 carbon atoms such asmethyl, ethyl, propyl, butyl or pentyl and the like; lower alkanoylradicals preferably contain from 2-5 carbons, examples being acetyl,propionyl, butyryl or valeryl and the like.

Also within the scope of the present invention are the alkali metal andalkaline earth metal salts of those triazoles where R₁ is hydrogen, suchas the sodium, potassium, and calcium salts, and the pharmaceuticallyacceptable quaternary salts such as the methiodides and ethiodides,mineral acid salts such as the hydrochloride or sulfate salts of thosecompounds wherein the substituent in the 3 and/or 5 position contains atleast one basic nitrogen, such as a pyridine ring. Also contemplated bythe invention are the N-oxides of a nitrogen heterocycle substituent inthe 3 or 5 position.

The following class of products are particularly effective xanthineoxidase inhibitors and, therefore, represent a preferred embodiment ofthis invention: ##STR2## wherein R₆ is pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, quinolyl, furyl, thienyl, halophenyl, for example,3-chlorophenyl or 4-chlorophenyl and the like, dihalophenyl, forexample, 3,4-dichlorophenyl or 3,5-dichlorophenyl and the like, or halo-and dihalosulfamoylphenyl, for example, 3-sulfamoyl4-chlorophenyl, or3,4-dichloro-5-sulfamoylphenyl and the like and R₇ is pyridyl,pyridylmethyl, pyrimidinyl or pyrazinyl, with the proviso that when R₆is pyridyl R₇ is other than pyridyl. The above products and thenon-toxic salts thereof, including the alkali metal and alkaline earthmetal salts, are especially effective anti-gout and anti-hyperuricemicagents and, therefore, represent a preferred subclass of compoundswithin the scope of this invention.

Those compounds corresponding to Formula Ib wherein R₇ is pyridyl,pyrazinyl or pyrimidinyl, and R₆ is halophenyl, dihalo-sulfamoyphenyl,thienyl, pyrazinyl, furyl, quinolyl, pyrimidinyl or pyridazinylrepresent an especially preferred subclass of compounds within the scopeof the present invention. Most preferred among the preferred compoundsare those wherein R₇ is pyridyl and R₆ is halophenyl.

In addition to their utility as anti-gout and anti-hyperuricemic agents,the following products are useful as diuretics and hypotensive agents:##STR3## wherein R₈ is halophenyl or dihalophenyl, as for example,3-chlorophenyl, 4-chlorophenyl or 3,4-dichlorophenyl and the like and R₉is pyridyl. The above-described products are characterized by theirability to reduce the concentration of sodium and chloride ions in thebody, lower dangerous excesses of fluid levels to acceptable limits and,in general, alleviate conditions usually associated with edema.

The compounds of Formulas I and Ia can be prepared by a series ofreactions which are depicted in the following flow diagram: ##STR4##wherein R₁ is hydrogen or loweralkyl and R₃ and R₅ are as defined above,and W is loweralkyl wherein the alkyl group contains 1-5 carbons. Aswill be appreciated by those skilled in this art, Compounds I and Ia arethe same when R₁ is hydrogen.

As can be seen from the above reaction diagram, a substituted hydrazinecompound such as, for example, isonicotinoylhydrazine, is reacted withan imino ester such as, for example ethyl p-chloroiminobenzoate, in asuitable solvent. Either lower boiling solvents, such as methanol orethanol, or nitromethane, or high boiling solvents, such as decalin,xylene, or dimethylsulfoxide, may be employed. When low boiling solventsare employed, the product of the reaction is usually the intermediateacylamidrazone. A reaction time of 3-20 hours at temperatures of fromroom temperature to the reflux temperature of the solvent is employed.The intermediate acylamidrazone II (III) may be converted to I (Ia) byheating it in the absence of solvent at temperatures between 125°-300°C. for from about 15 minutes to one hour or in higher boiling solventsat or near the reflux temperature of the solvent for from about one totwenty hours. The final cyclized product is isolated and purified bytechniques known in the art.

When high boiling solvents are employed, the reaction is convenientlycarried out at or near the reflux temperature of the solvent. Thepreferred temperature range is between 100°-200° C. The reaction time isdependent upon the particular temperature range employed. The reactionis carried out without isolation of the intermediate and the finalcyclized product is isolated and purified by techniques known in theart. For example, the product may be crystallized from a suitablesolvent, such as methanol or ethanol. As can be seen from the abovereaction diagram, where R₁ is loweralkyl, the selection of theparticular hydrazine compound and the particular imino ester will dependupon which substituent is desired in the 3 and/or 5 position.

Alternatively, the 1,2,4-triazoles of this invention can be prepared byreacting a suitable carbonitrile such as, for example, 4-cyanopyridine,with an alkali metal, such as sodium or potassium in a lower alkanol toform the imino ester. The imino ester is then reacted with a suitablecarboxylic acid hydrazide such as, for example, pyrazine carboxylic acidhydrazide, in a suitable solvent, such as methanol or ethanol. Thereaction mixture is first heated, preferably at reflux temperatures, forfrom about 1/2 to 20 hours, after which the reaction mixture isconcentrated by removal of the solvent, and the solid intermediate isheated at elevated temperatures, either in the presence or absence ofsolvent. When no solvent is employed, a temperature between 100°-300° C.for from about 15 minutes to one hour is preferred. The product iscollected by techniques known in the art. Where high boiling solventsare employed, the reaction is conveniently carried out at or near thereflux temperature of the solvent. The preferred temperature range is100°-200° C. The reaction time is dependent upon the particulartemperature range employed.

Those compounds having a substituent other than hydrogen in the 1position can also be prepared by reacting a triazole of Formula I whereR₁ is hydrogen with an appropriate alkylating or acylating agent. WhereR₃ and R₅ are different, a mixture of compounds is obtained, i.e. thesubstituent R₁ may be substituted on either one of the two adjacentnitrogens. For example, where the substituent is a loweralkanoyl groupsuch as an acetyl or butyryl group, the triazole is reacted with aloweralkyl anhydride such as, for example, acetic anhydride or butyricanhydride. Where the substituent in the 1 position is an alkyl group,alkylation is achieved by reacting the sodium salt of the triazole withan alkylating agent such as, for example, dimethylsulfate. Alkylation ofthe 1,2,4-triazoles generally occurs in the 1 position. Where the alkylgroup is a methyl group, methylation can be achieved by reacting thetriazole with diazomethane in a suitable solvent, such as diethylether.

Those compounds wherein the substituent in the 1 position is a carbamoylor substituted carbamoyl group are prepared by reacting a3,5-substituted-1,2,4-triazole with a carbamoyl halide such as, forexample, dimethylcarbamoyl chloride in a suitable solvent such astetrahydrofuran in the presence of a base, such as, for example, sodiumhydride.

An alternate method for preparing those compounds having an alkyl groupin the 1 position consists of first reacting a nitrile, such as, forexample, 4-cyanopyridine, with an alkali metal, such as sodium, in analcoholic solvent, such as methanol, at room temperature and adding tothis solution a hydrazide, such as, for example, a1-isonicotinoyl-2-loweralkylhydrazine. The reaction is heated, generallyat reflux temperature, for about 3-20 hours. Depending upon the natureof the substituent, the final cyclized product is obtained directly orthe intermediate acylamidrazone is obtained. In the case where theintermediate is obtained, it may be heated without solvent at about100°-300° C. for from about 15 minutes to several hours, or theintermediate can be heated in a high boiling solvent such as xylene ordecalin at about 100°-200° C. for about 1-20 hours. The alkylatedtriazole is isolated by techniques known in the art.

Those compounds of this invention which are amine oxides can be preparedby the method described above by employing a nitrile-N-oxide such as,for example, 4-cyanopyridine-N-oxide, as the nitrile reactant, or ahydrazine, such as pyridine-N-oxide-4-carboxylic acid hydrazide.

Representative examples of the compounds within the scope of thisinvention are:

3-(p-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole,

3-pyrazinyl-5-(4-pyridyl)-1,2,4-triazole,

3-(3,4-dichlorophenyl)-5-(4-pyridyl)-1,2,4-triazole,

1-ethyl-3,5-di(4-pyrimidyl)-1,2,4-triazole,

3-(6-quinolyl)-5-(4-pyridyl)-1,2,4-triazole,

3-(2-furyl)-5-(4-pyridyl)-1,2,4-triazole,

3-(4-chloro-3-sulfamoylphenyl)-5-(4-pyridyl)-1,2,4-triazole,

3-(3,5-dimethoxyphenyl)-5-(4-pyridyl)-1,2,4-triazole,

3-(m-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole,

3-(p-bromophenyl)-5-(4-pyridyl)-1,2,4-triazole,

3-(2-naphthyl)-5-(4-pyridyl)-1,2,4-triazole,

3-(3,4-dichloro-5-sulfamoylphenyl)-5-(4-pyridyl)-1,2,4-triazole,

3,5-di(4-pyrimidyl)-1,2,4-triazole,

N-methyl-4-[3-(p-chlorophenyl)-1,2,4-triazolyl-5]-pyridiniumiodide,

N-methyl-4-[3-(m-chlorophenyl)-1,2,4triazolyl-5]-pyridiniumiodide,

3-(p-chlorophenyl)-5-(4-pyridazinyl)-1,2,4-triazole,

1-butyryl-3-(p-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole,

1-acetyl-3-(3,4-dichlorophenyl)-5-(4-pyridyl)-1,2,4-triazole,

1-methyl-3-(3,5-dimethoxyphenyl)-5-(4-pyridyl)-1,2,4-triazole,

1-benzyl-3,5-di(4-pyrimidyl)-1,2,4-triazole,

3-(3,5-dimethoxyphenyl)-5-(2-pyrazinyl)-1,2,4-triazole,

3-(p-methoxyphenyl)-5-(3-pyridyl)-1,2,4-triazole,

3-(p-sulfamoylphenyl)-5-pyrazinyl-1,2,4-triazole,

1-methyl-3-(4-pyridyl)-5-(p-chlorophenyl)-1,2,4-triazole,

1-acetyl-3-(6-quinolyl)-5-(p-dimethylaminophenyl)-1,2,4-triazole,

and 1-methyl-3-(p-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole.

The substituted triazoles which are the subject of this inventioninhibit the action of the enzyme xanthine oxidase resulting in asignificant decrease in the concentration of uric acid in the blood andurine and are, therefore, capable of aborting attacks of gout.

For testing purposes, xanthine oxidase obtained from milk may beemployed to demonstrate the ability of the substituted triazoles toinhibit the enzyme. The general procedure is to employ a 5-10 unitsuspension of the enzyme per milliliter of 60% saturated ammoniumsulfate of the enzyme; 1 unit of such a suspension converts 1 μmole ofxanthine to uric acid per minute. Generally, for a 1-day assay, about0.05 ml. of enzyme is diluted with about 3 ml. of buffer. As the buffer,tris buffer (0.05 mole, pH 7.4) may be employed. The inhibitor to betreated is dissolved in buffer or a suitable solvent, such asdimethylsulfoxide; the same solvent is used to dilute the solution. Thebuffer, hypoxanthine and solvent are placed in a cell, and the enzymesolution is then added, and the rate of increase in absorbance at 290mμis noted with a recording spectrophotometer. Generally, sufficientenzyme is employed to give about 0.1 absorbance units change per minute,and sufficient inhibitor is used to give 30-70% inhibition. The μMconcentration of inhibitor necessary for 50% inhibition (V₀ /V₁ = 2) isdetermined by plotting V₀ /V₁ against I, where V₀ = velocity withoutinhibitor, V₁ = velocity with inhibitor, and I = inhibitorconcentration.

The therapeutically active substituted triazoles can be administered asthe active ingredient in association with a pharmaceutically acceptablecarrier in the form of tablets, elixirs, capsules, and the like. Thesepreparations may be made by any of the known pharmaceutical methods. Forexample, in tablet form, they are compounded with an inertpharmaceutical carrier which may contain a suitable binder such as, forexample, gums, starches, and sugars. They may also be incorporated intoa gelatin capsule or formulated into elixirs which have the advantage ofbeing susceptible to manipulations in flavor by the addition of standardnatural or synthetic flavoring materials. The compound is generallyadministered in compositions which are so proportioned as to afford aunit dosage of about 30 mg. to 1.5 gm. per day. The preferred dosagelevel, however, is about 100-800 mg. per day.

The following examples serve to illustrate typical tablet, capsule, andelixir formulations incorporating the therapeutically active substitutedtriazoles of this invention:

    ______________________________________                                        FORMULATION I - COMPRESSED TABLET COMPRISING                                  0.5 GM. OF ACTIVE INGREDIENT                                                  INGREDIENT           AMOUNT - MG.                                             ______________________________________                                        3-(p-chlorophenyl)-5-(4-pyridyl)-                                             1,2,4-triazole       500.0                                                    Starch paste - 121/2 12.5100 cc. allow.                                                            512.5                                                    Starch, U.S.P. Corn  25.0                                                     Magnesium stearate   5.5                                                                           543.0                                                    ______________________________________                                    

The 3-(p-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole is granulated withthe starch paste and while moist passed through a No. 14 screen, driedat 45° C. for 20 hours, and then passed 3 times through a No. 14 screen.The starch is then passed through a No. 90 bolting cloth onto thegranulation, and all ingredients are blended thoroughly. The magnesiumstearate is passed through a No. 90 bolting cloth onto the granulation,and these ingredients are blended, after which the granulation iscompressed into tablets using a 14/32inch flat, bevelled, scored punchhaving a thickness of 0.205 ± 0.005inch yielding 1,000 tablets eachweighing 0.543 grams.

    ______________________________________                                        FORMULATION II:                                                               ENCAPSULATION - FOR 250 MG. CAPSULE                                           INGREDIENT           AMOUNT - MG.                                             ______________________________________                                        3-pyrazinyl-5-(4-pyridyl)-1,2,4-                                              triazole             250                                                      Lactose               93                                                      Talc                  7                                                       ______________________________________                                    

Blend lactose, talc and the 3-pyrazinyl-5-(4-pyridyl)-1,2,4-triazole insuitable blending equipment, and encapsulate into a No. 2 capsule at atarget weight of 350 mg.

    ______________________________________                                        FORMULATION III: LIQUID SUSPENSION - FORMULA                                  INGREDIENT            AMOUNT - g./l.                                          ______________________________________                                        Veegum H.V.           3.0                                                     Water                 150.0                                                   Methyl paraben        1.0                                                     1-methyl-5-(4-pyridyl)-3-(p-chloro-                                           phenyl)-1,2,4-triazole                                                                              50.0                                                    Kaolin                10.0                                                    Flavor                1.0                                                     Glycerin, 9.5 to 1 liter                                                      ______________________________________                                    

Suspend Veegum in water with vigorous agitation, add methyl paraben andallow to stand overnight to ensure complete hydration of Veegum. Inseparate vessel suspend1-methyl-5-(4-pyridyl)-3-(p-chlorophenyl)-1,2,4-triazole in about 750cc. of glycerin. Add kaolin and stir until homogeneous. Slowly addaqueous dispersion of Veegum and methyl paraben. Add flavor and continueagitation for 1 hour to ensure homogeneity. Q.S. with remaining glycerinto 1:1. Stir until homogeneous. 1 Teaspoonful contains 250 mg. of1-methyl-5-(4-pyridyl)-3-(p-chlorophenyl)-1,2,4-triazole.

The following examples are given for purposes of illustration and not byway of limitation:

EXAMPLE 1 3-PYRAZINYL-5-(4-PYRIDYL)-1,2,4-TRIAZOLE

Sodium(0.4 grams) is added to pyridine-4-carbonitrile (8.3 grams, 0.08mole) in methanol, and the solution is allowed to stand 30 minutes atroom temperature. A suspension of pyrazine carboxylic acid hydrazide(9.6 grams, 0.07 mole) in methanol (160 ml.) is added, and the resultingsolution is heated at reflux for 30 minutes. After cooling, theintermediate acylamidrazone is collected by filtration. The acyclicintermediate is then heated at 260° C. for 15 minutes, after which thereaction is cooled to room temperature. Upon recrystallization fromacetonitrile-water, 3-pyrazinyl-5-(4-pyridyl)-1,2,4-triazole isobtained, m.p. 251°-252.5° C.

EXAMPLES 2 - 22

The following compounds are prepared by the reaction procedure describedin Example 1:

    __________________________________________________________________________    EX.                                                                              HYDRAZIDE   NITRILE  COMPOUND        MELTING POINT                         __________________________________________________________________________    2  3,4-dichlorobenzoyl-                                                                      4-cyanopyridine                                                                        5-(4-pyridyl(-3-(3,4-dichloro-                                                                345-346.5° C.                     hydrazine            phenyl)-1,2,4-triazole                                3  6-quinolinecarboxylic                                                                     4-cyanopyridine                                                                        5-(4-pyridyl)-3-(6-quinolyl)-                                                                 313-314.5° C.                     acid hydrazide       1,2,4-triazole                                        4  3-pyridyl acetic acid                                                                     4-cyanopyridine                                                                        3-(3-picolyl)-5-(4-pyridyl)-                                                                  161-162° C.                       hydrazide            1,2,4-triazole                                        5  2-furoic acid hydrazide                                                                   4-cyanopyridine                                                                        5-(4-pyridyl)-3-(2-furyl)-                                                                    216-217° C.                                            1,2,4-triazole                                        6  4-chloro-3-sulfamoyl-                                                                     4-cyanopyridine                                                                        5-(4-pyridyl)-3-(4-chloro-3-                                                                  335.5-336.5° C.                   benzoyl hydrazine    sulfamoylphenyl)-1,2,4-triazole                       7  3,5-dimethoxy-                                                                            4-cyanopyridine                                                                        5-(4-pyridyl)-3-(3,5-dimethoxy-                                                               252-253.5° C.                     benzoylhydrazine     phenyl)-1,2,4-triazole                                8  m-chlorobenzoyl-                                                                          4-cyanopyridine                                                                        5-(4-pyridyl)-3-(m-chlorophenyl)-                                                             269-271° C.                       hydrazine            1,2,4-triazole                                        9  pyrazinecarboxylic                                                                        2-cyanopyridine                                                                        5-(2-pyridyl)-3-pyrazinyl-1,2,4-                                                              248-250° C.                       acid hydrazide       triazole                                              10 isonicotinic acid                                                                         2-cyanopyrimidine                                                                      5-(4-pyridyl)-3-(2-pyrimidinyl)-                                                              274-276° C.                       hydrazide            1,2,4-triazole                                        11 3,5-dichlorobenzoyl-                                                                      4-cyanopyridine                                                                        5-(4-pyridyl)-3-(3,5-dichloro-                                                                298-299.5° C.                     hydrazine            phenyl)-1,2,4-triazole                                12 p-bromobenzoyl-                                                                           4-cyanopyridine                                                                        5-(4-pyridyl)-3-(p-bromophenyl)-                                                              263-264° C.                       hydrazine            1,2,4-triazole                                        13 4-pyridazinecarboxylic                                                                    4-cyanopyridine                                                                        5-(4-pyridyl)-3-(4-pyridazinyl)-                                                              276-278° C.                       acid hydrazide       1,2,4-triazole                                        14 p-methoxybenzoyl                                                                          4-cyanopyridine                                                                        5-(4-pyridyl)-3-(p-methoxy-                                                                   247-249° C.                       hydrazine            phenyl)-1,2,4-triazole                                15 2-thiophenecarboxylic                                                                     4-cyanopyridine                                                                        5-(4-pyridyl)-3-(2-thienyl)-                                                                  240-241.5° C.                     acid hydrazide       1,2,4-triazole                                        16 p-sulfamoylbenzoyl-                                                                       4-cyanopyridine                                                                        5-(4-pyridyl)-3-(p-sulfamoyl                                                                  301-302° C.                       hydrazine            phenyl)-1,2,4-triazole                                17 2-naphthoic acid                                                                          4-cyanopyridine                                                                        5-(4-pyridyl)-3-(2-naphthyl)-                                                                 289-390° C.                       hydrazide            1,2,4-triazole                                        18 3,4-dichloro-5-                                                                           4-cyanopyridine                                                                        5-(4-pyridyl)-3-(3,4-dichloro-                                                                330° C. (dec.)                    sulfamoylbenzoyl-    5-sulfamoylphenyl)-1,2,4-                                hydrazine            triazole                                              19 2-pyridylacetic                                                                           4-cyanopyridine                                                                        5-(4-pyridyl)-3-(2-picolyl)-                                                                  190-191° C.                       acid hydrazide       1,2,4-triazole                                        20 isonicotinic acid                                                                         4-cyanopyrimidine                                                                      5-(4-pyridyl)-3-(4-pyrimidinyl)-                                                              285-286.5° C.                     hydrazide            1,2,4-triazole                                        21 4-pyrimidinecarboxylic                                                                    4-cyanopyrimidine                                                                      3,5-di(4-pyrimidinyl)-1,2,4-                                                                  302-304° C.                       acid hydrazide       triazole                                              22 2,4-dichloro-5-                                                                           4-cyanopyridine                                                                        5-(4-pyridyl)-3-(2,4-dichloro-                                                                297-299° C.                       sulfamoylbenzoyl-    5-sulfamoylphenyl)-1,2,4-                                hydrazine            triazole                                              __________________________________________________________________________

EXAMPLE 23 3-(p-CHLOROPHENYL)-5-(4-PYRIDYL)-1,2,4-TRIAZOLE

To a suspension of isonicotinoylhydrazine (10.9 grams, 0.08 mole) inmethanol (250 ml.) is added a solution of ethyl p-chloroiminobenzoate(14 grams, 0.08 mole) in methanol (50 ml.). The reaction mixture isrefluxed for 30 minutes and is then concentrated until a solid separatesout of solution. The mixture is then cooled, and the intermediateacylamidrazone is collected by filtration. The acyclic intermediate isthen heated at 280° C. for 15 minutes, after which it is cooled to roomtemperature. Upon recrystallization from ethanol-water and sublimation,3-(p-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole is obtained, m.p.264.5°-265.5° C.

EXAMPLE 24 N-METHYL-4-[3-(p-CHLOROPHENYL)-1,2,4-TRIAZOLYL-5]-PYRIDINIUMIODIDE

To a suspension of 3-(p-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole (1gram, 0.004 mole) in N,N-dimethylformamide (25 ml.) is added methyliodide (1.4 grams, 0.01 mole), and the resulting solution is allowed tostand at room temperature for one hour. The solid which separates duringthe reaction is collected by filtration. Upon recrystallization frommethanol, N-methyl-4-[3-(p-chlorophenyl)-1,2,4-triazolyl-5]-pyridiniumiodide is obtained, m.p. 275° C.

When in the above procedure3-(m-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole is employed in place of3-(p-chlorophenyl)-5 -(4-pyridyl)-1,2,4-triazole,N-methyl-4-[3-(m-chlorophenyl)-1,2,4-triazolyl-5]-pyridinium iodide isobtained, m.p. 280°-281° C.

EXAMPLE 25 3,5-DIPYRAZINYL-1,2,4-TRIAZOLE

Sodium (50 mg.) is added to 2-cyanopyrazine (1 gram, 0.01 mole) in 20ml. of methanol. The solution is allowed to stand 1 hour at roomtemperature and is added to a suspension of pyrazine carboxylic acidhydrazide (1.4 grams, 0.01 mole) in 50 ml. of methanol. The reactionmixture is heated at reflux for 2 hours and then at room temperature for16 hours. After cooling, the intermediate acylamidrazone is removed byfiltration and is then heated at temperatures between 200° to 260° C.over two and one-half hours. After cooling and recrystallization frommethanol-water, 0.8 grams of 3,5-dipyrazinyl-1,2,4-triazole, m.p.269°-270.5° C. is obtained.

EXAMPLE 26 1-ACETYL-3,5-DIPYRAZINYL-1,2,4-TRIAZOLE

A suspension of 3,5-dipyrazinyl-1,2,4-triazole (0.5 grams) in 20 ml. ofacetic anhydride is heated on a steam bath for 17 hours. The resultingsolution is filtered and concentrated to a solid. Afterrecrystallization from benzene-hexane, 250 mg. of1-acetyl-3,5-dipyrazinyl-1,2,4-triazole is obtained, m.p. 128°-130° C.

EXAMPLE 27 1-DIMETHYLCARBAMOYL-3,5-DIPYRAZINYL-1,2,4-TRIAZOLE

To 2.25 g. (0.01 mole) of 3,5-dipyrazinyl-1,2,4-triazole in 200 ml. oftetrahydrofuran is added 57% sodium hydride (.42 g., 0.01 mole). Thereaction mixture is heated at reflux for one hour, cooled, and asolution of dimethylcarbamoyl chloride (1 gram, 0.01 mole) in 10 ml. oftetrahydrofuran is added dropwise. The reaction mixture is then refluxedfour hours, cooled, filtered and concentrated to a solid. Afterrecrystallization from benzene1-dimethylcarbamoyl-3,5-dipyrazinyl-1,2,4-triazole is obtained.

EXAMPLE 28 3-(p-AMINOPHENYL)-5-(4-PYRIDYL)-1,2,4-TRIAZOLE

To 4-cyanopyridine (4.2 g.) in methanol (60 ml.) is added sodium (0.2g.). The solution is allowed to stand for 0.5 hour at room temperatureand is then added to a suspension of p-aminobenzhydrazide (6.4 g.) in150 ml. of methanol. The resulting solution is heated 20 hours at refluxduring which time a solid separates. The solid is filtered and heated to245° C. over one hour and maintained at that temperature for anadditional 15 minutes. After cooling the solid is recrystallized from amixture of acetonitrile and water to yield3-(p-aminophenyl)-5-(4-pyridyl)-1,2,4-triazole (2 g.) m.p. 251°-252.5°C.

Analysis calculated for C₁₃ H₁₁ N₅. Calculated: C,65.81; H,4.67;N,29.52. Found: C,65.95; H,4.71; N,29.61.

Upon substituting p-(dimethylamino)benzoylhydrazine and3-cinnolylcarbohydrazine for p-aminobenzhydrazide in the above methodand otherwise following the procedure described therein, there is thusobtained 3-(p-dimethylaminophenyl)-5-(4-pyridyl)-1,2,4-triazole and3-(3-cinnolyl)-5-(4-pyridyl)-1,2,4-triazole.

EXAMPLE 29 3-(p-ACETYLAMINOPHENYL)-5-(4-PYRIDYL)-1,2,4-TRIAZOLE

To 3-(p-aminophenyl)-5-(4-pyridyl)-1,2,4-triazole (1 g.) is added aceticanhydride (20 ml.) and the resulting suspension is heated 18 hours on asteam bath. The excess acetic anhydride is removed under reducedpressure and water (25 ml.) is added to the residue. After stirring 0.5hour, the solid is filtered and recrystallized to yield3-(p-acetylaminophenyl)-5-(4-pyridyl)-1,2,4-triazole.

EXAMPLE 30 1-METHYL-3-(p-CHLOROPHENYL)-5-(4-PYRIDYL)-1,2,4-TRIAZOLE

To 4-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.).After standing at room temperature 0.5 hour the solution is added to1-methyl-2-p-chlorobenzoylhydrazine (3.6 g.) in methanol (40 ml.). Thereaction mixture is refluxed for 5 hours and concentrated to an oilwhich is solidified. After recrystallization from ethyl alcohol 0.5 g.of 1-methyl-3-(p-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole m.p. 191° C.is obtained.

Analysis calculated for C₁₄ H₁₁ ClN₄. Calculated: N,20.70; C,62.11;H,4.10. Found: N,20.66; C,62.07; H,4.06.

Upon substituting 3-cyanopyridine for 4-cyanopyridine in the abovemethod and otherwise following the procedure described therein there isthus obtained 1-methyl-3-(p-chlorophenyl)-5-(3-pyridyl)-1,2,4-triazolem.p. 157°-158.5° C.

Analysis calculated for C₁₄ H₁₁ ClN₄. Calculated: N,20.70; C,62.11;H,4.10. Found: N,20.61; C,62.12; H,4.10.

EXAMPLE 31 1-METHYL-3-(4-PYRIMIDINYL)-5-(4-PYRIDYL)-1,2,4-TRIAZOLE and1-METHYL-3-(4-PYRIDYL)-5-(4-PYRIMIDINYL)-1,2,4-TRIAZOLE

To 3-(4-pyrimidinyl)-5-(4-pyridyl)-1,2,4-triazole (2.2 g.) in drytetrahydrofuran (125 ml.) is added 57% sodium hydride in mineral oil(0.46 g.). After refluxing 0.5 hour, methyliodide (1.4 g.) is added andthe mixture is heated an additional three hours at reflux. The reactionmixture is cooled, filtered and concentrated to a solid. The solid istriturated with water and filtered to yield a mixture of1-methyl-3-(4-pyrimidinyl)-5-(4-pyridyl)-1,2,4-triazole, and1-methyl-3-(4-pyridyl)-5-(4-pyrimidinyl)-1,2,4-triazole.

EXAMPLE 32 1-BENZYL-3,5-bis(4-PYRIMIDINYL)-1,2,4-TRIAZOLE

To 3,5-bis(4-pyrimidinyl)-1,2,4-triazole (4.5 g.) in dry tetrahydrofuran(200 ml.) is added 57% sodium hydride in mineral oil (0.93 g.). Themixture is heated at reflux for 45 minutes, cooled and concentrated to asolid which is then dissolved in N,N-dimethylformamide (70 ml.).Benzylchloride (2.8 g.) is added and the solution is heated for fourhours on a steam bath. The reaction mixture is concentrated to a gum,water is added and the resulting solid is removed by filtration. Afterrecrystallization substantially pure1-benzyl-3,5-bis(4-pyrimidinyl)-1,2,4-triazole is obtained.

EXAMPLE 33 1-METHYL-3,5-bis(4-PYRIMIDINYL)-1,2,4-TRIAZOLE

To 3,5-bis(4-pyrimidinyl)-1,2,4-triazole (2.3 g.) in dry tetrahydrofuran(125 ml.) is added 57% sodium hydride in mineral oil (0.46 g.). Afterrefluxing 0.5 hour, methyl iodide (1.4 g.) is added and the mixture isheated at reflux an additional three hours. The reaction mixture iscooled, filtered and concentrated to a solid which afterrecrystallization yields substantially pure1-methyl-3,5-bis(4-pyrimidinyl)-1,2,4-triazole.

EXAMPLE 34 1-CARBAMOYL-3-(4-PYRIMIDINYL)-5-(4-PYRIDYL)-1,2,4-TRIAZOLEand 1-CARBAMOYL-3-(4-PYRIDYL)-5-(4-PYRIMIDINYL)-1,2,4-TRIAZOLE

To 3-(4-pyrimidinyl)-5-(4-pyridyl)-1,2,4-triazole (4.5 g.) in drytetrahydrofuran (20 ml.) is added 57% sodium hydride in mineral oil(0.93 g.). The mixture is heated at reflux for 0.5 hour, cooled and asaturated solution of phosgene in tetrahydrofuran (50 ml.) is addeddropwise with stirring at room temperature. After one hour the solutionis concentrated to one-half volume and added dropwise to a saturatedsolution of ammonia in ethanol (100 ml.). After one hour the mixture isconcentrated to a solid, aqueous sodium carbonate solution is added andthe resulting solid filtered to yield a mixture of1-carbamoyl-3-(4-pyrimidinyl)-5-(4-pyridyl)-1,2,4-triazole and1-carbamoyl-3-(4-pyridyl)-5-(4-pyrimidinyl)-1,2,4-triazole.

Any departure from the above description which conforms to the presentinvention is intended to be included within the scope of the claims.

What is claimed is:
 1. A compound of the formula ##STR5## and the amineoxides and non-toxic salts thereof, wherein R₁ is hydrogen, lower alkyl,lower alkanoyl, benzyl, carbamoyl or di- lower alkylcarbamoyl;R₃ isnapthyl, halophenyl, dihalophenyl, aminophenyl, diloweralkylaminophenyl,loweralkanoylaminophenyl, monoloweralkoxyphenyl, or diloweralkoxyphenyland R₅ is pyridyl.
 2. A compound of the formula: ##STR6## and thenon-toxic salts thereof; wherein R₈ is halophenyl or dihalophenyl and R₉is pyridyl.
 3. A compound of claim 2 selectedfrom5-(4-pyridyl)-3-(3,4-dichlorophenyl)-1,2,4-triazole,5-(4-pyridyl)-3-(m-chlorophenyl)-1,2,4-triazole,5-(4-pyridyl)-3-(3,5-dichlorophenyl)-1,2,4-triazole,5-(4-pyridyl)-3-(p-bromophenyl)-1,2,4-triazole, or5-(4-pyridyl)-3-(p-chlorophenyl)-1,2,4-triazole.
 4. A compound selectedfromN-methyl-4-[2-(p-chlorophenyl)-1,2,4-triazolyl-5]-pyridinium iodide,1-methyl-3-(p-chlorophenyl-5-(4-pyridyl)-1,2,4-triazole,3-(p-aminophenyl)-5-(4-pyridyl)-1,2,4-triazole,3-(p-acetylaminophenyl)-5-(4-pyridyl)-1,2,4-triazole,1-butyryl-3-(p-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole,N-methyl-4-[3-(m-chlorophenyl)-1,2,4-triazolyl-5] pyridinium iodide,1-methyl-3-(p chlorophenyl)-5-(3-pyridyl)1,2,4-triazole,3-(p-dimethylaminophenyl)-5-(4-pyridyl)-1,2,4-triazole,1-acetyl-3-(3-dichlorophenyl)-5-(4-pyridyl-1,2,4-triazole, or1-methyl-3-(3,5-dimethoxyphenyl)-5-(4-pyridyl)-1,2,4-triazole.
 5. Acompound having the formula ##STR7## and the amine oxides and nontoxicsalts thereof wherein R₃ is mono- or di-loweralkoxyphenyl andR₅ ispryidyl.
 6. A compound of claim 5 selected from3-(3,5-dimethoxyphenyl)-5-(4-pyridyl)-1,2,4-triazole or3-(p-methoxyphenyl)-5-(3-pyridyl)-1,2,4-triazole.